Pulmonary lymphangioleiomyomatosis (LAM) is an uncommon disorder that occurs almost exclusively in women of childbearing age. The clinical presentation of LAM is quite distinctive and includes recurrent spontaneous pneumothorax, chylothorax, hemoptysis, chylous ascites and slowly progressive dyspnea. The cardinal histopathologic finding is a remarkable proliferation of immature-appearing, disorganized smooth muscle cells in the lung and along axial lymphatics in the thorax and abdomen. It is likely that most clinical symptoms and signs of LAM are due to abnormal smooth cell proliferation. The abnormal smooth muscle cells in LAM are shorter, plumper, and have a higher ratio of nucleus to cytoplasm than normal smooth muscle cells. Interestingly, these abnormal smooth muscle cells, unlike their normal counterparts in airways or blood vessels, react with monoclonal antibody HMB45, which reacts with a 100- kDa glycoprotein (termed gp100) found in human melanoma cells. To characterize the antigens recognized by HMB45, normal human lung tissue, lung specimens from four patients with LAM, and cells from three melanoma cell lines (Malme-3M, A2058, and CHL-1) were subjected to Northern analysis, immunohistochemical and electron microscopic studies as well as Northern analysis using a full-length gp100 cDNA probe generated by reverse transcription-polymerase chain reaction from total RNA isolated from Malme-3M cells. Levels of gp100 mRNA were highest in Malme-3M cells, followed by A2058 cells, and then lung tissue of individuals with LAM; it was not detected in normal lung or CHL-1 cells. Immunohistochemical staining for HMB45 was intense in Malme-3M cells, and less in A2058 cells and lung tissue of individuals with LAM. HMBYS reactivity; it was not detected in normal lung or CHL-1 cells. Electron-dense small granules with a fine lamellar structure in the cytoplasm of abnormal smooth muscle cells in LAM lung were detected by electron microscopy. These granules resembled immature melanosomes in Malme-3M cells. Further, these electron-dense granules contained HMB45-binding sites as demonstrated by immunoelectron microscopy.